Blood vessel diameter is an important component of blood pressure (BP) regulation and slight alterations in diameter can have profound effects that can result in hypertension. The beta-adrenergic receptor (bAR) system plays a critical role in BP control. In animal models and human hypertension, there are impairments in dilatory bAR signaling including increased levels and activity of G protein-coupled receptor (GPCR) kinases (GRKs) 2 and 5, which desensitize bARs (b1 and b2 subtypes) and other GPCRs. Typically, bARs are coupled to the heterotrimeric G protein, Gs, and mediate increases in protein kinase A (PKA) activity resulting in dilation via phosphorylation of several down-stream targets. PKA also phosphorylates b2ARs rendering them capable of coupling to Gi heterotrimeric proteins. Normally b1ARs are not capable of this Gi switching because of a physical interaction with the PSD-95 protein, however, phosphorylation of b1ARs by GRK5, and not GRK2, dissociates PSD-95 allowing for Gi-coupling. Importantly, Gi-mediated signaling elicits constriction in VSM and inhibition with pertussis toxin in animal models of high BP is an effective antihypertensive strategy. Thus, alterations in bAR (b1 and b2) signaling including novel protein-protein interactions induced via phosphorylation and desensitization by specific GRKs may have a significant impact on vessel diameter and BP. Accordingly, we developed transgenic mice with VSM-specific overexpression of GRK2 or GRK5 in order to recapitulate an important aspect of hypertension and to use these mouse models to understand the direct impact that specific GRK activity has on bAR-mediated signaling in VSM in vivo. Our overall hypothesis is that increased expression of GRK2 or GRK5 in VSM has a direct impact on the signaling of bARs which may influence BP regulation and hypertension. Specific VSM GRK phosphorylation of bARs may impair dilation and alter novel receptor interactions with signaling proteins including PSD-95 (b1ARs) and Gi (b1- and b2ARs). Our specific aims are: 1.To determine the effect of increased VSM GRK2 or GRK5 expression and activity on bAR signaling in vitro using primary VSM cells isolated from VSM-targeted GRK transgenic mice. 2. To determine the effect of VSM-specific GRK2 or GRK5 overexpression on bAR signaling pathways in the functional regulation of isolated blood vessels. 3. To determine the in vivo role of GRK2 and GRK5 on bAR signaling and vascular regulation in hypertension.